Sequencing Therapies in NSCLC

Benjamin P. Levy: I think there is a large group of patients who progress on chemotherapy, whose tumors are growing on frontline chemotherapy, in whom immunotherapy should be considered the standard of care. These are patients who’ve received 4 cycles of chemotherapy and then went on to get maintenance chemotherapy, and they’re doing very well. Once they progress, I think immunotherapy is with pembrolizumab, atezolizumab, or nivolumab. I think it’s a very reasonable option for these patients. And we’ve seen in multiple data sets that immunotherapy outperforms docetaxel in intention-to-treat analysis across the board. There are certain circumstances where immunotherapy may not be used, but overall, I think immunotherapy is a very reasonable strategy for a lot of our patients second-line.

A patient who is rapidly progressing with a low PD-L1 score in frontline is a patient who I may consider for docetaxel/ramucirumab. Or for a patient with a low PD-L1 who’s very symptomatic after first-line, again, this is a consideration where immunotherapy may not be the best drug. Treatment decisions have to be individualized, so this is a scenario where I would consider using docetaxel with an antiangiogenic strategy.

I think we’ve had so many new therapies approved in non–small cell lung cancer that there has to be a lot of consideration and a lot of thought that goes in to how to sequence treatments, given that there are competing options.

I’ll just give you my approach. For patients who come in and don’t have a driver mutation, these patients I generally start on carboplatin/pemetrexed. If they have at least achieved stable disease and if they can tolerate it, I put them on maintenance. Now, if they’re on maintenance, their tumor is growing, and they’re not that symptomatic, or if they are symptomatic, these patients I would generally put on immunotherapy in the second-line, no doubt. Every patient warrants immunotherapy unless they have some sort of contraindication. Every patient needs to have a consideration for immunotherapy. So, for these patients, I would give a second-line immunotherapy approach.

For patients whom I start on chemotherapy, however, who have rapidly progressing disease and have a low PD-L1, these are patients with whom I have a discussion about the role of immunotherapy versus docetaxel with ramucirumab. And, again, the goal here is to improve outcomes, to improve response rates, to improve quality of life, and to improve survival. So, I think we have to be very careful with these patients.

If patients are rapidly progressing, they’re symptomatic, and their PD-L1 score is very low, this is where I’m not saying I wouldn’t use immunotherapy in these patients, but I would certainly consider other alternatives as well. If I use bevacizumab up front—and I do that for probably 10% to 15% of my patients—then patients are progressing and rapidly progressing, that’s a consideration, again, for docetaxel/ramucirumab. For patients who aren’t rapidly progressing second-line, I use immunotherapy. And even for patients who are on maintenance and whose tumors start to grow quickly, I would still consider immunotherapy for second-line. I think the consideration is if a patient is not responding to frontline chemotherapy, they’re moving quickly, they’re symptomatic, and their PD-L1 score is low. Maybe immunotherapy is not the best option for these patients.

Things get a lot more confusing when you add targets in there. You have EGFR and ALK, and how to sequence those therapies gets even more complicated. But for the nondriver disease, it’s usually chemotherapy followed by immunotherapy. For certain circumstances, I will use chemotherapy if they’re rapidly progressing, followed by more chemotherapy. I don’t use immunotherapy yet up front with carboplatin/pemetrexed. I may change that, and if you bring me back in 6 months, I may have a different answer based on the phase III trial. I don’t think it’s unreasonable to do, I’m just not there yet in my own practice.

I would just say, in closing, that we’re in a very exciting time, and I’ve said that before. We really are now in a very exciting time for lung cancer, not just with the incorporation of immunotherapy. I think we’re starting to just scratch the surface with immunotherapy. Trying to understand how to harness the immune system against cancer is something that we’ve been trying to do for 30, 40, 50 years, and we’re finally figuring out, “OK, there’s a way to do this.” Now we have to look at combination strategies with immunotherapy and then targeted therapies. We are now really better understanding the genetic underpinnings of a tumor.

Targets are going to go way beyond EGFR, ALK, ROS, and BRAF. Comprehensive genomic profiling is now inexpensive. It can be done, and we’re going to identify more and more targets that we can then give genotype-driven therapies for. So, I’m very excited on the 2 fronts. It’s a very fascinating time. And then, the final thing I’ll mention is the whole idea of liquid biopsies. This is not something that we talked about, but using liquid biopsies to make treatment decisions—not only in the refractory setting, but also up front and even as early detection—is very promising.